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Guest Editorial

Review Article

J Biomech Eng. 2016;138(11):110801-110801-11. doi:10.1115/1.4034428.

The microvasculature is an extensive, heterogeneous, and complex system that plays a critical role in human physiology and disease. It nourishes almost all living human cells and maintains a local microenvironment that is vital for tissue and organ function. Operating under a state of continuous flow, with an intricate architecture despite its small caliber, and subject to a multitude of biophysical and biochemical stimuli, the microvasculature can be a complex subject to study in the laboratory setting. Engineered microvessels provide an ideal platform that recapitulates essential elements of in vivo physiology and allows study of the microvasculature in a precise and reproducible way. Here, we review relevant structural and functional vascular biology, discuss different methods to engineer microvessels, and explore the applications of this exciting tool for the study of human disease.

Commentary by Dr. Valentin Fuster

Research Papers

J Biomech Eng. 2016;138(11):111001-111001-9. doi:10.1115/1.4034559.

Patient-specific biventricular computational models associated with a normal subject and a pulmonary arterial hypertension (PAH) patient were developed to investigate the disease effects on ventricular mechanics. These models were developed using geometry reconstructed from magnetic resonance (MR) images, and constitutive descriptors of passive and active mechanics in cardiac tissues. Model parameter values associated with ventricular mechanical properties and myofiber architecture were obtained by fitting the models with measured pressure–volume loops and circumferential strain calculated from MR images using a hyperelastic warping method. Results show that the peak right ventricle (RV) pressure was substantially higher in the PAH patient (65 mmHg versus 20 mmHg), who also has a significantly reduced ejection fraction (EF) in both ventricles (left ventricle (LV): 39% versus 66% and RV: 18% versus 64%). Peak systolic circumferential strain was comparatively lower in both the left ventricle (LV) and RV free wall (RVFW) of the PAH patient (LV: −6.8% versus −13.2% and RVFW: −2.1% versus −9.4%). Passive stiffness, contractility, and myofiber stress in the PAH patient were all found to be substantially increased in both ventricles, whereas septum wall in the PAH patient possessed a smaller curvature than that in the LV free wall. Simulations using the PAH model revealed an approximately linear relationship between the septum curvature and the transseptal pressure gradient at both early-diastole and end-systole. These findings suggest that PAH can induce LV remodeling, and septum curvature measurements may be useful in quantifying transseptal pressure gradient in PAH patients.

Commentary by Dr. Valentin Fuster
J Biomech Eng. 2016;138(11):111002-111002-5. doi:10.1115/1.4034561.

Benchtop in vitro experiments are valuable tools for investigating the cardiovascular system and testing medical devices. Accurate reproduction of the physiologic flow waveforms at various anatomic locations is an important component of these experimental methods. This study discusses the design, construction, and testing of a low-cost and fully programmable pulsatile flow pump capable of continuously producing unlimited cycles of physiologic waveforms. It consists of a gear pump actuated by an AC servomotor and a feedback algorithm to achieve highly accurate reproduction of flow waveforms for flow rates up to 300 ml/s across a range of loading conditions. The iterative feedback algorithm uses the flow error values in one iteration to modify the motor control waveform for the next iteration to better match the desired flow. Within four to seven iterations of feedback, the pump replicated desired physiologic flow waveforms to within 2% normalized RMS error (for flow rates above 20 mL/s) under varying downstream impedances. This pump device is significantly more affordable (∼10% of the cost) than current commercial options. More importantly, the pump can be controlled via common scientific software and thus easily implemented into large automation frameworks.

Commentary by Dr. Valentin Fuster
J Biomech Eng. 2016;138(11):111003-111003-8. doi:10.1115/1.4034656.
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In a properly contracting cardiac muscle, many different subcellular structures are organized into an intricate architecture. While it has been observed that this organization is altered in pathological conditions, the relationship between length-scales and architecture has not been properly explored. In this work, we utilize a variety of architecture metrics to quantify organization and consistency of single structures over multiple scales, from subcellular to tissue scale as well as correlation of organization of multiple structures. Specifically, as the best way to characterize cardiac tissues, we chose the orientational and co-orientational order parameters (COOPs). Similarly, neonatal rat ventricular myocytes were selected for their consistent architectural behavior. The engineered cells and tissues were stained for four architectural structures: actin, tubulin, sarcomeric z-lines, and nuclei. We applied the orientational metrics to cardiac cells of various shapes, isotropic cardiac tissues, and anisotropic globally aligned tissues. With these novel tools, we discovered: (1) the relationship between cellular shape and consistency of self-assembly; (2) the length-scales at which unguided tissues self-organize; and (3) the correlation or lack thereof between organization of actin fibrils, sarcomeric z-lines, tubulin fibrils, and nuclei. All of these together elucidate some of the current mysteries in the relationship between force production and architecture, while raising more questions about the effect of guidance cues on self-assembly function. These types of metrics are the future of quantitative tissue engineering in cardiovascular biomechanics.

Commentary by Dr. Valentin Fuster
J Biomech Eng. 2016;138(11):111004-111004-11. doi:10.1115/1.4034826.

In a monocrotaline (MCT) induced-pulmonary arterial hypertension (PAH) rat animal model, the dynamic stress–strain relation was investigated in the circumferential and axial directions using a linear elastic response model within the quasi-linear viscoelasticity theory framework. Right and left pulmonary arterial segments (RPA and LPA) were mechanically tested in a tubular biaxial device at the early stage (1 week post-MCT treatment) and at the advanced stage of the disease (4 weeks post-MCT treatment). The vessels were tested circumferentially at the in vivo axial length with matching in vivo measured pressure ranges. Subsequently, the vessels were tested axially at the mean pulmonary arterial pressure by stretching them from in vivo plus 5% of their length. Parameter estimation showed that the LPA and RPA remodel at different rates: axially, both vessels decreased in Young's modulus at the early stage of the disease, and increased at the advanced disease stage. Circumferentially, the Young's modulus increased in advanced PAH, but it was only significant in the RPA. The damping properties also changed in PAH; in the LPA relaxation times decreased continuously as the disease progressed, while in the RPA they initially increased and then decreased. Our modeling efforts were corroborated by the restructuring organization of the fibers imaged under multiphoton microscopy, where the collagen fibers become strongly aligned to the 45 deg angle in the RPA from an uncrimped and randomly organized state. Additionally, collagen content increased almost 10% in the RPA from the placebo to advanced PAH.

Commentary by Dr. Valentin Fuster
J Biomech Eng. 2016;138(11):111005-111005-11. doi:10.1115/1.4034655.

Optogenetic approaches allow cellular membrane potentials to be perturbed by light. When applied to muscle cells, mechanical events can be controlled through a process that could be termed “optomechanics.” Besides functioning as an optical on/off switch, we hypothesized that optomechanical control could include the ability to manipulate the strength and duration of contraction events. To explore this possibility, we constructed an electromechanical model of the human ventricular cardiomyocyte while adding a representation of channelrhodopsin-2 (ChR2), a light-activated channel commonly used in optogenetics. Two hybrid stimulus protocols were developed that combined light-based stimuli with traditional electrical current (all-or-none) excitation. The first protocol involved delivery of a subthreshold optical stimulus followed 50–90 ms later by an electrical stimulus. The result was a graded inhibition of peak cellular twitch force in concert with a prolongation of the intracellular Ca2+ transient. The second protocol was comprised of an electrical stimulus followed by a long light pulse (250–350 ms) that acted to prolong the cardiac action potential (AP). This created a pulse duration-dependent prolongation of the intracellular Ca2+ transient that in turn altered the rate of muscle relaxation without changing peak twitch force. These results illustrate the feasibility of acute, optomechanical manipulation of cardiomyocyte contraction and suggest that this approach could be used to probe the dynamic behavior of the cardiac sarcomere without altering its intrinsic properties. Other experimentally meaningful stimulus protocols could be designed by making use of the optomechanical cardiomyocyte model presented here.

Commentary by Dr. Valentin Fuster
J Biomech Eng. 2016;138(11):111006-111006-9. doi:10.1115/1.4034621.

Quantification of the tricuspid valve (TV) leaflets mechanical strain is important in order to understand valve pathophysiology and to develop effective treatment strategies. Many of the traditional methods used to dynamically open and close the cardiac valves in vitro via flow simulators require valve dissection. Recent studies, however, have shown that restriction of the atrioventricular valve annuli could significantly change their in vivo deformation. For the first time, the porcine valve leaflets deformation was measured in a passive ex vivo beating heart without isolating and remounting the valve annuli. In particular, the right ventricular apexes of porcine hearts (n = 8) were connected to a pulse-duplicator pump that maintained a pulsatile flow from and to a reservoir connected to the right atrium and the pulmonary arteries. This pump provided a right ventricular pressure (RVP) waveform that closely matched physiological values, leading to opening and closure of the tricuspid and pulmonary valves (PVs). At the midsection of the valve leaflets, the peak areal strain was 9.8 ± 2.0% (mean±standard error). The peak strain was 5.6 ± 1.1% and 4.3 ± 1.0% in the circumferential and radial directions, respectively. Although the right ventricle was beating passively, the leaflet peak areal strains closely matched the values measured in other atrioventricular valves (i.e., the mitral valve (MV)) in vivo. This technique can be used to measure leaflet strains with and without the presence of valve lesions to help develop/evaluate treatment strategies to restore normal valve deformation.

Commentary by Dr. Valentin Fuster
J Biomech Eng. 2016;138(11):111007-111007-8. doi:10.1115/1.4034560.

Amyloid beta accumulation in neuronal and cerebrovascular tissue is a key precursor to development of Alzheimer's disease and can result in neurodegeneration. While its persistence in Alzheimer's cases is well-studied, amyloid beta's direct effect on vascular function is unclear. Here, we measured the effect of amyloid beta treatment on vascular smooth muscle cell functional contractility and modeled the mechanoadaptive growth and remodeling response to these functional perturbations. We found that the amyloid beta 1-42 isoform induced a reduction in vascular smooth muscle cell mechanical output and reduced response to vasocontractile cues. These data were used to develop a thin-walled constrained mixture arterial model that suggests vessel growth, and remodeling in response to amyloid betamediated alteration of smooth muscle function leads to decreased ability of cerebrovascular vessels to vasodilate. These findings provide a possible explanation for the vascular injury and malfunction often associated with the development of neurodegeneration in Alzheimer's disease.

Commentary by Dr. Valentin Fuster

Technical Brief

J Biomech Eng. 2016;138(11):114501-114501-6. doi:10.1115/1.4034558.
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Myocardial contractility of the left ventricle (LV) plays an essential role in maintaining normal pump function. A recent ex vivo experimental study showed that cardiomyocyte force generation varies across the three myocardial layers of the LV wall. However, the in vivo distribution of myocardial contractile force is still unclear. The current study was designed to investigate the in vivo transmural distribution of myocardial contractility using a noninvasive computational approach. For this purpose, four cases with different transmural distributions of maximum isometric tension (Tmax) and/or reference sarcomere length (lR) were tested with animal-specific finite element (FE) models, in combination with magnetic resonance imaging (MRI), pressure catheterization, and numerical optimization. Results of the current study showed that the best fit with in vivo MRI-derived deformation was obtained when Tmax assumed different values in the subendocardium, midmyocardium, and subepicardium with transmurally varying lR. These results are consistent with recent ex vivo experimental studies, which showed that the midmyocardium produces more contractile force than the other transmural layers. The systolic strain calculated from the best-fit FE model was in good agreement with MRI data. Therefore, the proposed noninvasive approach has the capability to predict the transmural distribution of myocardial contractility. Moreover, FE models with a nonuniform distribution of myocardial contractility could provide a better representation of LV function and be used to investigate the effects of transmural changes due to heart disease.

Commentary by Dr. Valentin Fuster

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